DESCRIPTION: The development of the inner ear is controlled by the coordinated expression of many genes. These include, but are not limited to, genes encoding transcription factors as well as growth factors and their receptors. In the current application, they propose to study the role played by two of these gene families, which appear to be interrelated, in cochlear development. Members of the POU-domain gene family of transcription factors are expressed at high levels in the developing inner ear, and a member of this family has recently been shown to be involved in X-linked deafness with stapes fixation. They will explore the effects of targeted mutations (of) three POU-domain genes on inner ear development. Preliminary data indicate that knockout of Brn-3.0 leads to abnormal migration of developing spiral ganglion (SG) neurons; knockout of Brn-3.1 leads to complete failure of cell development; while knockout of Brn-3.2 leads to reduced density of spiral ganglion neurons. The nature of these phenotypes will be documented, and the mechanisms which produce them will be explored. They will also document the effects of in vitro transfection with Brn-3.1, associated with the hair cell phenotype, on cells in the developing neuroepithelium. A second group of studies will assess the role of growth factors in organ of Corti and spiral ganglion development. Acidic fibroblast growth factor (FGF-1) is expressed by cochlear hair cells in the first postnatal weeks, and by SG neurons from birth onward. They will explore the role of this expression by identifying the FGF receptors expressed on developing cochlear cells, and documenting the effects of exogenous FGF-1 as well as FGF receptor blockade on cochlear development in vitro.